Design, synthesis, characterization and antimicrobial evaluation of some novel hydrazinecarbothioamide, 4-thiazolidinone and 1,2,4-triazole-3-thione derivatives

Article abstract of DOI:10.1002/jhet.4159

A series of novel hydrazinecarbothioamide (5a,c,f), 4-thiazolidinone (6a-e), and 1,2,4-triazole-3-thione (7a-d) were designed and synthesized. The structural elucidations of the novel compounds were performed by IR, ¹H-NMR, ¹³C-NMR, mass and elemental analysis. All novel derivatives were evaluated for their antibacterial and antifungal activities against nine diverse microorganisms. According to the biological activity studies of the compounds, 6d, 7c and 7d displayed hope promising antibacterial activity. Furthermore, 6d displayed potent antifungal activity. Consequently, the obtained results revealed that 6d, 7c and 7d present a leading structure for future drug development due to its straightforward synthesis and relevant bioactivity.

Full text of DOI:10.1002/jhet.4159

Design, synthesis, characterization and antimicrobial evaluation of some novel
hydrazinecarbothioamide, 4-thiazolidinone and 1,2,4-triazole-3-thione derivatives
Efe Doğukan Dincel1,*, Nuray Ulusoy-Güzeldemirci1, Dilek Şatana2, Ömer Küçükbasmacı3
1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, İstanbul University,
34116, İstanbul, Turkey
2
Department of Microbiology, İstanbul Faculty of Medicine, İstanbul University, 34093,
İstanbul, Turkey
3
Department of Microbiology, Cerrahpaşa Faculty of Medicine, İstanbul University
Cerrahpaşa, 34098, İstanbul, Turkey
*Correspondence:
Pharmacist, Efe Doğukan Dincel, Department of Pharmaceutical Chemistry, Faculty of
Pharmacy, İstanbul University, 34116, İstanbul, Turkey
Email: efe.dincel@istanbul.edu.tr
orcid.org/0000-0002-5445-0600
Abstract
A series of novel hydrazinecarbothioamide (5a,c,f), 4-thiazolidinone (6a-e), and 1,2,4-
triazole-3-thione (7a-d) were designed and synthesized. The structural elucidations of the
1
13
novel compounds were performed by IR, H-NMR, C-NMR, mass and elemental analysis.
All novel derivatives were evaluated for their antibacterial and antifungal activities against 9
diverse microorganisms. According to the biological activity studies of the compounds, 6d, 7c
and 7d displayed hope promising antibacterial activity. Furthermore, 6d displayed potent
antifungal activity. Consequently, the obtained results revealed that 6d, 7c and 7d present a
leading structure for future drug development due to its straightforward synthesis and relevant
bioactivity.
KEYWORDS synthesis, structure elucidation, hydrazinecarbothioamide, 4-thiazolidinone,
1,2,4-triazole-3-thione, antimicrobial activity,
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1 INTRODUCTION
The sharply rising level of antibiotic-resistant bacterias, which was speeded up by the misuse
of antibiotics, has become a significant and global health problem.[1] Day by day, an
increasing number of infection based diseases caused by resistant bacterias have been failing
to respond to conventional treatment and in some cases, even last-resort antibiotics have lost
their curative effect.[2] Besides that, infections stemming from fungal microorganisms have
been continuing to increase swiftly because of the enormous number of immunocompromised
patients and easily gained resistance.[3, 4] Since the sharply rising level of multi-drug resistant
microorganisms, the discovery of novel compounds to overcome these microorganisms has
become one of the major issues of pharmaceutical chemistry today.[5]
Triazoles are members of heterocyclic compounds possessing a five-membered ring, that
bears two carbon atoms and three nitrogen atoms.[6,7] Triazole derivatives have attracted the
interest of researchers due to their wide range of biologic activities like anticonvulsant,[8]
antidepressant,[9] antioxidant,[10] anti-inflammatory,[11] analgesic,[12] antinociceptive,[13]
antibacterial,[14-16] antimycobacterial,[17] antifungal,[15,16,18,19] antiviral,[20] anticancer,[21,22] anti-
parasitic,[23] 5α-reductase inhibitory,[24] and anti-urease,[25] . Also, there are known drugs
which are currently being used in the treatment and contain 1,2,4-triazole moiety like
fluconazole (antifungal), itraconazole (antifungal), voriconazole (antifungal), rizatriptan (5-
hydroxytryptamine 1 receptor subtype agonist/migraine) and ribavirin (antiviral) (Figure 1).
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Figure 1 Chemical structures of some drugs bearing 1,2,4-triazole moiety
4-Thiazolidinones are thiazolidine derivatives which possess a sulfur atom at position one, a
nitrogen atom at position three, and a carbonyl group at position four. 4-Thiazolidinones have
been considered as a pharmacologically active scaffold due to their wide range of reported
biological activities in literature. The compounds bearing 4-thiazolidinone moiety have been
reported in the literature by their antibacterial,[26] antifungal,[27,28] antitubercular,[29]
anticancer,[30-33] anti-inflammatory,[34] analgesic,[35] anticonvulsant,[36]
antiviral,[37,38]
cytotoxic,[39] and antidiabetic[40] activities. Compounds such as ralitoline (anticonvulsant),
pioglitazone (hypoglycemic) and thiazolidomycin (activity against Streptomyces species),
based on 4-thiazolidinone pharmacophore are already in clinical use as commercial products
(Figure 2).
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Figure 2 Chemical structures of some drugs bearing 4-thiazolidinone moiety
Thiosemicarbazide moiety bearing compounds have been considered as biologically
important since their wide range of reported biological activity such as antibacterial,[41,42]
antifungal,[43] antitubercular,[44] anticonvulsant,[45] anticancer,[46,47] cytotoxic[42] and
antioxidant[48]. Thiosemicarbazide moiety is not only important because of their potential
activity but also their ability to be used as starting compounds for the synthesis of diverse
biologically potent moieties such as 1,2,4-triazole-3-thiones,[48] 4-thiazolidinones,[49] 1,3,4-
oxadiazoles[11] and 1,3,4-thiadiazoles.[11] Antitubercular thioacetazone, anticancer triapine and
methisazone are drug molecules that are used in treatment currently and bearing
thiosemicarbazide/thiosemicarbazone moiety (Figure 3).
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Figure 3 Chemical structures of some drugs bearing thiosemicarbazide/thiosemicarbazone
moiety
In this study, the design, synthesis, structure elucidation, antibacterial and antifungal activity
studies of novel thiosemicarbazide, 1,2,4-triazole and 4-thiazolidinone derivatives were
reported. Structural characterizations of the synthesized compounds were performed by IR
1
13
spectroscopy, H-NMR, C-NMR, mass spectrometry and elemental analysis. Antibacterial
activities of the synthesized compounds were evaluated against S. aureus (ATCC 29213), E.
coli (ATCC 25922) and P. aeruginosa (ATCC27853). Besides that, antifungal activities of the
novel compounds were evaluated against C. albicans (ATCC10231), C. krusei (ATCC 6258),
C. parapsilosis (ATCC 22019), M. gypseum (NCPF580), T. metagrophytes var. erinacei
(NCPF 375) and T. tonsurans (NCPF 245).
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2 RESULTS AND DISCUSSION
2.1 Chemistry
The title compounds (5a, 5c, 5f, 6a-e and 7a-d) (Table 1) were synthesized from furoic acid
hydrazide by a five and six-step synthesis through the pathways displayed in Figure 4 and
Figure 5. Furoic acid hydrazide and 4-bromophenyl isothiocyanate were refluxed in ethanol to
yield N-(4-bromophenyl)-2-(furan-2-carbonyl)hydrazinecarbothioamide (1). Thereafter, a
solution of compound 1 in 2N aqueous NaOH was refluxed. After cooling, the reaction
mixture was acidified by 12.5% aqueous HCI and thus 4-(4-bromophenyl)-5-(furan-2-yl)-2,4-
dihydro-3H-1,2,4-triazole-3-thione (2) was obtained. Compound 2 and ethyl bromoacetate
were refluxed in ethanol in the presence of KOH to obtain ethyl 2-((4-(4-bromophenyl)-5-
(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (3). By heating compound 3 and hydrazine
hydrate
in
ethanol,
2-((4-(4-bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-
yl)thio)acetohydrazide (4) was yielded. The compound 4 and substituted isothiocyanates were
refluxed in ethanol to yield 2-(2-((4-(4-bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-
yl)thio)acetyl)-N-(alkyl/allyl/aryl)hydrazinecarbothioamides (5a-f). 5a-f, ethyl bromoacetate
and fused sodium acetate were refluxed in ethanol to yield 2-((4-(4-bromophenyl)-5-(furan-2-
yl)-4H-1,2,4-triazol-3-yl)thio)-N’-(3-(alkyl/allyl/aryl)-4-oxothiazolidin-2-
ylidene)acetohydrazides (6a-e). 5a-f were heated in 2N aqueous NaOH under reflux. After
cooling, the reaction mixture was acidified by 12.5% aqueous HCI and in this way 5-(((4-(4-
bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-4-(alkyl/allyl)-2,4-dihydro-
3H-1,2,4-triazole-3-thiones (7a-d) were yielded. The reaction yields of the novel compounds
5a,c,f, 6a-e and 7a-d were between the interval of 99.50%-83.23%, 97.14%-81.74% and
98.75%-75.70% respectively.
When the chemical structures of the synthesized compounds were examined, it was observed
that there is just one carbonyl group belonging 5a,c,f which is found in the hydrazide
functional group of the mentioned compounds. Besides that, there are two carbonyl groups,
which are found in the hydrazone moiety and 4-thiazolidinone moiety of 6a-e. Moreover,
there is no carbonyl group belonging 7a-d. Also according to the IR spectroscopy results, the
stretching bands belonging to the carbonyl groups of hydrazide functional group of 5a,c,f
were able to be observed in the range of 1710-1688 cm-1 and there wasn’t a secondary
carbonyl peak belonging a secondary carbonyl group. Moreover, the stretching bands
belonging to the carbonyl groups of hydrazone moiety and 4-thiazolidinone ring of 6a-e were
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in the range of 1684-1645 cm-1 and 1727-1716 cm-1 respectively. No band belonging to a
carbonyl group was observed for 7a-d.
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The IR values belonging to the mentioned carbonyl groups of 5a,c,f and 6a-e were in
agreement with the literature.[49-52]
According to the literature, N-H proton belonging the hydrazide group of compound 4 was
observed in 9.48 ppm as a broad singlet and also the NH2 protons were observed in 3.45 ppm
as a broad singlet. When the results obtained from compound 5a,c,f were examined, it was
determined that the peaks of NH2 protons were disappeared and totally three diverse N-H
proton were observed in the region of 10.30-8.16 ppm. This results indicated the formation of
thiosemicarbazide derivatives from compound 3. N-H peak of 6a-e and 7a-d were observed in
the range of 10.56 – 10.49 and 13.69-13.58 ppm respectively and just one N-H peak was
observed for each of the mentioned compounds. Decreasing of the number of N-H peaks from
three to one, indicated the formation of 6a-e and 7a-d from 5a-e. The peaks of SCH2 protons
of 5a,c,f and 7a-d were determined in the range of 4.09-3.88 and 4.36-4.33 ppm respectively.
The peak integration values of the mentioned SCH2 peaks were 2H since there is just one
SCH2 group belonging 5a,c,f and 7a-d. The SCH2 protons belonging 6a-e were determined in
the range of 4.17-3.95 ppm. Unlike 5a,c,f and 7a-d, the integration value of the SCH2 peaks
of 6a-e were determined as 4H since there are two diverse SCH2 group in 6a-e.
1
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The IR, H NMR, C NMR and mass spectra of the novel compounds were in compliance
with the assigned structures and the literature.[49-52] No unacceptable side reactions were
observed, and the desired products were obtained in moderate to good yields.
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Table 1 Some physicochemical and analytical data of the compounds bearing
thiosemicarbazide (5a-f), 4-thiazolidinone (6a-e) and 1,2,4-triazole-3-thione (7a-d) moiety
Compound
R
Formula (MW) M.p. (oC) Yield (%)
CH3
C16H15BrN6O2S2 176-177
(467.37)
93.92
83.23
99.50
81.74
97.14
88.11
88.23
82.35
75.70
93.28
92.78
98.75
5a
C3H7
C18H19BrN6O2S2 203-204
(495.42)
5c
5f
C6H4CH3(4-) C22H19BrN6O2S2 185-186
(543.46)
CH3
C2H5
C3H7
C18H15BrN6O3S2 222-223
(507.39)
6a
6b
6c
6d
6e
7a
7b
7c
7d
C19H17BrN6O3S2 164-165
(521.42)
C20H19BrN6O3S2 171-172
(535.44)
CH2-CH=CH2 C20H17BrN6O3S2 174-175
(533.43)
C6H5
C23H17BrN6O3S2 222-223
(569.46)
CH3
C16H13BrN6OS2 218-220
(449.35)
C2H5
C3H7
C17H15BrN6OS2 258-259
(463.38)
C18H17BrN6OS2 263-264
(477.41)
CH2-CH=CH2 C18H15BrN6OS2 249-250
(475.39)
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Figure 4 Synthesis of the starting compounds 1, 2, 3 and 4
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Figure 5 Synthesis of the title compounds
2.2 Biological activity
All of the title compounds were evaluated for in vitro antibacterial activity against S. aureus
ATCC 29213, E. coli ATCC 25922, P. aeruginosa ATCC 27853 as well as for antifungal
activity against C. albicans ATCC 10231, C. krusei ATCC 6258, C. parapsilosis ATCC
22019, M. gypseum NCPF580, T. mentagrophytes var. erinacei, T. tonsurans NCPF245 using
the microbroth dilution method (Table 2, Table 3). As can be seen in Table 1, 6d (R = CH2-
CH=CH2), 7c (R = C3H7) and 7d (R = CH2-CH=CH2) showed the highest activity against S.
aureus ATCC 29213 (MIC = 32 µg/mL). Besides, 7c (R = C3H7) and 7d (R = CH2-CH=CH2)
displayed the highest activity against E. coli ATCC 25922 (MIC = 32 µg/mL). In addition, 7d
(R = CH2-CH=CH2) displayed the highest activity against P. aeruginosa ATCC 27853 (MIC
= 32 µg/mL). Generally, 1,2,4-triazole-3-thione derivatives displayed higher antibacterial
activity than thiosemicarbazide and 4-thiazolidinone derivatives against S. aureus ATCC
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29213, E. coli ATCC 25922 and P. aeruginosa ATCC 27853. Propyl and allyl substitution of
4-position of the 1,2,4-triazole-3-thione ring increased the antibacterial activity. Besides, 3-
allyl substitution of 4-thiazolidinone ring increased the antibacterial activity of 4-
thiazolidinone derivatives. This indicated the importance of the mentioned N-allyl
substitutions for antibacterial activity of 1,2,4-triazole-3-thione and 4-thiazolidinone
derivatives.
Table 2 Antibacterial activity of the title compounds (5a,c,f, 6a-e, 7a-d) (MIC µg/mL)
Compound
Microorganismsa
A
B
64
C
> 64
> 64
64
64
5a
> 64
> 64
> 64
64
> 64
> 64
> 64
> 64
> 64
64
5c
5f
> 64
> 64
> 64
32
6a
6b
64
6c
64
6d
64
> 64
64
> 64
64
6e
64
7a
> 64
32
64
> 64
64
7b
32
7c
7d
32
32
32
0.12
0.015
0.5
Levofloxacin
a A = S. aureus ATCC 29213, B = E. coli ATCC 25922, C = P. aeruginosa ATCC 27853
6d was determined as the most active compound against C. albicans ATCC 10231 (MIC = 16
µg/mL), C. parapsilosis ATCC 22019 (MIC = 8 µg/mL), T. mentagrophytes var. erinacei
NCPF375 (MIC = 8 µg/mL) and T. tonsurans NCPF245 (MIC = 8 µg/mL). 6c, 6d, 7c and 7d
displayed the highest activity against C. krusei ATCC 6258 (MIC = 16 µg/mL). 6a, 6b, 6d,
7a, 7c and 7d displayed the highest activity against M. gypseum NCPF580 (MIC = 16
µg/mL). Generally, 1,2,4-triazole-3-thione and 4-thiazolidinone derivatives displayed higher
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antifungal activity than thiosemicarbazide derivatives. Besides, the most active antifungal
compound was
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determined as 6d (MIC = 16 µg/mL for C. albicans ATCC 10231, MIC = 16 µg/mL for C.
krusei ATCC 6258, MIC = 8 µg/mL for C. parapsilosis ATCC 22019, MIC = 16 µg/mL for
M. gypseum NCPF580, MIC = 8 µg/mL for T. mentagrophytes var. erinacei NCPF375 and T.
tonsurans NCPF245), which has an allyl group at the 3-position of the 4-thiazolidinone ring.
This indicated that, 3-allyl substitution of 4-thiazolidinone ring is not only important for their
antibacterial activity but also their antifungal activity.
Table 3 Antifungal activity of the title compounds (5a,c,f, 6a-e, 7a-d) (MIC µg/mL)
Compound
Microorganismsa
A
32
32
64
32
64
32
16
32
32
64
32
32
0.12
n.t.
B
32
32
32
32
32
16
16
64
32
64
16
16
0.12
n.t.
C
D
32
32
64
16
16
32
16
32
16
64
16
16
n.t.
0.5
E
16
32
32
16
16
16
8
F
16
32
32
16
16
32
8
32
32
64
16
32
16
8
5a
5c
5f
6a
6b
6c
6d
64
32
64
16
16
0.06
n.t.
64
16
64
16
32
n.t.
0.5
64
16
64
16
16
n.t.
0.25
6e
7a
7b
7c
7d
Itraconazole
Amphotericin B
a A = C. albicans ATCC 10231, B = C. krusei ATCC 6258, C = C. parapsilosis ATCC 22019,
D = M. gypseum NCPF580, E = T. mentagrophytes var. erinacei NCPF375, F = T. tonsurans
NCPF245
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3 CONCLUSION
In the present study, in an attempt to discover novel antibacterial and antifungal agents, 12
diverse derivatives of thiosemicarbazide, 4-thiazolidinone and 1,2,4-triazole-3-thione were
designed and synthesized. Structural elucidation of the synthesized compounds was
1
performed and verified by IR spectroscopy, H-NMR, 13C-NMR, mass spectrometry and
elemental analysis.
The compounds were screened for their antibacterial and antifungal activity against diverse
microorganisms. Moreover, the structure activity relationships of the title compounds were
examined and evaluated.
As a summary, 6d, 7c and 7d were determined as the most active antibacterial compounds.
Generally, 1,2,4-triazole-3-thione derivatives displayed higher antibacterial activity than
thiosemicarbazide and 4-thiazolidinone derivatives. Propyl and allyl substitution of 4-position
of 1,2,4 triazole-3-thione ring and 3-allyl substitution of 4-thiazolidinone ring increased the
antibacterial activity of the compounds. This underlined the significance of the stated N-allyl
substitution for antibacterial activity of 1,2,4-triazole-3-thione and 4-thiazolidinone
derivatives.
Compound 6d, which has an allyl group at the 3-position of 4-thiazolidinone ring, was also
found as the most active antifungal compounds within our compounds. This indicated that 3-
allyl substitution of 4-thiazolidinones is not only important for their antibacterial activity but
also their antifungal activity.
The findings revealed the promising antibacterial and antifungal activity of thiosemicarbazide,
1,2,4-triazole-3-thione and 4-thiazolidinone derivatives and these derivatives could be an
interesting starting point for further structural optimization to obtain novel promising and
more potent antimicrobial agents.
4 EXPERIMENTAL
4.1 Chemistry
4.1.1 General
IR spectra were recorded on KBr discs, using a Shimadzu IR Affinity-1 FT-IR instrument. 1H
NMR (500 MHz) and 13C NMR (125 MHz) spectra were recorded on Varian UNITY INOVA
spectrometer in DMSO-d6 solution. Chemical shifts (δ) were reported in ppm; coupling
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constants (J) were recorded in hertz (Hz). Mass spectra were obtained on a VG Zab Spec (70
eV) instrument. The reactions were monitored by TLC aluminum plates with silica gel
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Kieselgel 60 F254 thickness 0.25 mm (Merck), using UV light as a visualizing agent. All
reagents and solvents were purchased from Merck, Fluka and Sigma-Aldrich and were used
without further purification.
4.1.2 General procedure for the synthesis of compounds 1-4
The starting compounds 1-4 were prepared as described in the literature.[50-51]
2-((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide (4)
The analytical and spectral data belonging compound 4 were described in the literature as
following:[53-55]
o
M.p. 171-172 C. IR υmax (KBr, cm-1): 3627, 3567 (N-H stretching); 1671 (C=O stretching).
1H-NMR (400 MHz, CDCI3 + DMSO-d6): 9.48 (br.s., 1H, NH), 7.66 (d, J = 8.6 Hz, 2H, ar),
7.47 (d, J = 3.7Hz, 1H, C5-H), 7.29 (d, J = 8.6 Hz, 2H, ar), 6.37 (dd, J = 3.5 ; 1.8 Hz, 1H, C4-
H), 6.23 (d, J = 3.5 Hz, 1H, C3-H), 3.81, (s, 2H, SCH2), 3.45 (br.s., 1H, NH2).
4.1.3 General procedure for the synthesis of 2-(2-((4-(4-bromophenyl)-5-(furan-2-yl)-4H-
1,2,4-triazol-3-yl)thio)acetyl)-N-(alkyl/alkenyl/aryl)hydrazinecarbothioamides (5a-f)
0.005 mol various substituted isothiocyanates were added to a solution of 0.005 mol 2-((4-(4-
bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetohydrazide in 20 mL of absolute
ethanol and heated in a water bath for 3 hours under reflux. After cooling, the precipitate was
separated and purified either by washing with hot EtOH or recrystallization from EtOH.
2-(2-((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetyl)-N-
methylhydrazinecarbothioamide (5a)
White solid, m.p. 176-177 oC, yield: 93.92%. Anal. Calcd. for C16H15BrN6O2S2: C, 41.11; H,
3.23; N, 17.98 %. Found: C, 41.38; H, 3.31; N, 17.62 %. IR υmax (KBr, cm-1): 3280 (N-H
stretching), 1705 (C=O stretching), 1542, 1513, 1491, 1450 (C=N, C=C stretching). 1H-NMR
(500 MHz) (DMSO-d6/TMS) δ (ppm): 10.19 (s, 1H, NH), 9.35 (s, 1H, NH), 8.22 (s, 1H, NH),
7.84 (d, J = 8.30 Hz, 2H, BrPh), 7.77 (d, J = 1.95 Hz, 1H, furan C5-H), 7.51 (d, J = 8.30 Hz,
2H, BrPh), 6.54 (dd, J = 3.41 ; 1.95 Hz, 1H, furan C4-H), 6.31 (d, J = 3.41 Hz, 1H, furan C3-
13
H), 3.89 (s, 2H, SCH2), 2.95 (s, 3H, CH3). C NMR (APT) (125 MHz, δ ppm, DMSO-d6):
182.63 (C=S), 167.08 (C=O), 151.94 (Fur C2), 147.72 (TR C5), 145.61 (Fur C5), 141.02 (TR
C3), 133.60 (BrPh C3,5), 133.11 (BrPh C1), 130.35 (BrPh C2,6), 124.51 (BrPh C4), 112.26
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(fur C3,4), 34.68 (CH2), 31.47 (CH3). EIMS [m/z (%)]: 468 [(M+2), 4], 466 (M+, 4), 395 (6),
393 (6), 364 (16), 362 (16), 323 (100), 321 (96), 269 (27), 267 (27), 250 (18), 248 (18).
2-(2-((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetyl)-N-
ethylhydrazinecarbothioamide (5b)
The analytical and spectral data belonging compound 5b were reported in the literature.[55]
2-(2-((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetyl)-N-
propylhydrazinecarbothioamide (5c)
White solid, m.p. 203-204 oC, yield: 83.23%. Anal. Calcd. for C18H19BrN6O2S2: C, 43.63; H,
3.86; N, 16.96 %. Found: C, 43.66; H, 3.97; N, 16.74 %. IR υmax (KBr, cm-1): 3341 (N-H
stretching), 1710 (C=O stretching), 1536, 1492, 1455, 1426 (C=N, C=C stretching). 1H-NMR
(500 MHz) (DMSO-d6/TMS) δ (ppm): 10.16 (s, 1H, NH), 9.27 (s, 1H, NH), 8.16 (s, 1H, NH),
7.84 (d, J = 8.30 Hz, 2H, BrPh), 7.78 (d, J = 1.96 Hz, 1H, furan C5-H), 7.50 (d, J = 8.78 Hz,
2H, BrPh), 6.54 (dd, J = 3.42, 1.95 Hz, 1H, furan C4-H), 6.31 (d, J = 3.41 Hz, 1H, furan C3-
H), 3.88 (s, 2H, SCH2), 3.45 (q, J = 6.83 Hz, 2H, N-CH2), 1.55 (sx, J = 6.83 Hz, 2H, CH2),
0.81 (t, J = 7.32 Hz, 3H, CH3).
2-(2-((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetyl)-N-
allylhydrazinecarbothioamide (5d)
The analytical and spectral data belonging compound 5d were reported in the literature.[55]
2-(2-((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetyl)-N-
phenylhydrazinecarbothioamide (5e)
The analytical and spectral data belonging compound 5e were reported in the literature.[55]
2-(2-((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)acetyl)-N-(4-
methylphenyl)hydrazinecarbothioamide (5f)
White solid, m.p. 185-186 oC, yield: 99.50%. Anal. Calcd. for C22H19BrN6O2S2: C, 48.62; H,
3.52; N, 15.46 %. Found: C, 48.42; H, 3.33; N, 15.19 %. IR υmax (KBr, cm-1): 3199 (N-H
stretching), 1688 (C=O stretching), 1593, 1514, 1490, 1424 (C=N, C=C stretching). 1H-NMR
(500 MHz) (DMSO-d6/TMS) δ (ppm): 10.30 (s, 1H, NH), 9.64 (s, 1H, NH), 9.60 (s, 1H, NH),
7.83; 7.80 (d, J = 8.30 ; 8.79 Hz, 2H, BrPh), 7.77 (d, J = 0.98 Hz, 1H, furan C5-H), 7.51-7.11
( m, 6H, ar.), 6.54 (dd, J = 3.91 ; 1.46 Hz, 1H, furan C4-H), 6.31 (d, J = 3.41 Hz, 1H, furan,
C3-H), 4.09 ; 3.95 (2s, 2H, SCH2), 2.35 ; 2.27 (2s, 3H, CH3).
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4.1.4 General procedure for the synthesis of 2-((4-(4-bromophenyl)-5-(furan-2-yl)-4H-
1,2,4-triazol-3-yl)thio)-N’-(3-(alkyl/alkenyl/aryl)-4-oxothiazolidin-2-
ylidene)acetohydrazides (6a-e)
A mixture of 0.005 mol 2-(2-((4-(4-bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-
yl)thio)acetyl)-N-(alkly/aryl)hydrazinecarbothioamide, 0.005 mol of ethyl bromoacetate, and
0.02 mol of fused sodium acetate in 25 mL anhydrous EtOH is heated under reflux for 3
hours. The reaction mixture is cooled, diluted with water, and allowed to stand overnight. The
precipitate was filtered, dried, and recrystallized from EtOH.
2-((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)-N’-(3-methyl-4-
oxothiazolidin-2-ylidene)acetohydrazide (6a)
White solid, m.p. 222-223 oC, yield: 81.74%. Anal. Calcd. for C18H15BrN6O3S2: C, 42.61; H,
2.97; N, 16.56 %. Found: C, 42.84; H, 3.17; N, 16.73 %. IR υmax (KBr, cm-1): 3232 (N-H
stretching), 1720 (C=O ring, stretching), 1645 (C=O stretching), 1592, 1509, 1491, 1446
1
(C=N, C=C stretching). H-NMR (500 MHz) (DMSO-d6/TMS) δ (ppm): 10.54 (s, 1H, NH),
7.81 (d, J = 8.79 Hz, 2H, BrPh), 7.76 (d, J = 0.97 Hz, 1H, furan C5-H), 7.48 (d, J = 8.30 Hz,
2H, BrPh), 6.53 (dd, J = 3.42 ; 1.96 Hz, 1H, furan C4-H), 6.31 (d, J = 3.41 Hz, 1H, furan C3-
13
H), 4.02 ; 4.01 (2s, 4H, SCH2), 3.06 (s, 3H, NCH3). C NMR (APT) (125 MHz, δ ppm,
DMSO-d6): 171.76 (ring C=O), 163.60 (C=O), 158.31 (C=N), 151.51 (Fur C2), 147.66 (TR
C5), 145.49 (Fur C5), 141.24 (TR C3), 133.48 (BrPh C3,5), 133.11 (BrPh C1), 130.40 (BrPh
C2,6), 124.31 (BrPh C4), 112.22; 112.05 (fur C3,4), 35.44 (ring CH2), 33.44 (CH2), 29.62
(CH3). EIMS [m/z (%)]: 508 [(M+2), 29], 506 (M+, 26), 364 (98), 362 (100), 323 (27), 321
(26), 269 (8), 267 (7), 250 (12), 248 (12).
2-((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)-N’-(3-ethyl-4-
oxothiazolidin-2-ylidene)acetohydrazide (6b)
White solid, m.p. 164-165 oC, yield: 97.14%. Anal. Calcd. for C19H17BrN6O3S2: C, 43.76; H,
3.28; N, 16.11 %. Found: C, 44.48; H, 3.96; 15.45 %. IR υmax (KBr, cm-1): 3473 (N-H
stretching), 1716 (C=O ring, stretching), 1684 (C=O stretching), 1603, 1513, 1493, 1456
1
(C=N, C=C stretching). H-NMR (500 MHz) (DMSO-d6/TMS) δ (ppm): 10.54 (s, 1H, NH),
7.82 (d, J =8.30 Hz, 2H, BrPh), 7.76 (d, J = 0.98 Hz, 1H, furan C5-H), 7.49 (d, J = 8.79 Hz,
2H, BrPh), 6.53 (dd, J =3.42 ; 1.95 Hz, 1H, furan C4-H), 6.31 (d, J = 2.93 Hz, 1H, furan C3-
H), 4.02 ; 4.01 (2s, 4H, SCH2), 3.65 ; 3.45 (2q, J = 7.32 Hz, 2H, N-CH2), 1.11 ; 1.06 (2t, J =
7.32 Hz, 3H, CH3).
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2-((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)-N’-(3-propyl-4-
oxothiazolidin-2-ylidene)acetohydrazide (6c)
White solid, m.p. 171-172 oC, yield: 88.11%. Anal. Calcd. for C20H19BrN6O3S2: C, 44.86; H,
3.57; N, 15.69 %. Found: C, 45.10; H, 4.09; N, 15.32 %. IR υmax (KBr, cm-1): 3473 (N-H
stretching), 1716 (C=O ring, stretching), 1683 (C=O stretching), 1601, 1513, 1492, 1457
1
(C=N, C=C stretching). H-NMR (500 MHz) (DMSO-d6/TMS) δ (ppm): 10.54 (s, 1H, NH),
7.80 (d, J = 8.78 Hz, 2H, BrPh), 7.76 (d, J = 1.47 Hz, 1H, furan C5-H), 7.48 (d, J = 8.78 Hz,
2H, BrPh), 6.53 (dd, J = 3.42 ; 1.96 Hz, 1H, furan C4-H), 6.31 (d, J = 3.41 Hz, 1H, furan C3-
H), 4.04; 4.00 (2s, 4H, SCH2), 3.58; 3.43 (2t, J = 7.32 Hz, 2H, N-CH2), 1.60-1.56 (m, 2H,
CH2), 1.04 ; 0.83 (2t, J = 7.32 Hz, 3H, CH3).
2-((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)-N’-(3-allyl-4-
oxothiazolidin-2-ylidene)acetohydrazide (6d)
White solid, m.p. 174-175 oC, yield: 88.23%. Anal. Calcd. for C20H17BrN6O3S2: C, 45.03; H,
3.21; N, 15.75 %. Found: C, 44.95; H, 3.84; N, 15.98 %. IR υmax (KBr, cm-1): 3473 (N-H
stretching), 1718 (C=O ring, stretching), 1670 (C=O stretching), 1602, 1512, 1492, 1424
1
(C=N, C=C stretching). H-NMR (500 MHz) (DMSO-d6/TMS) δ (ppm): 10.56 (s, 1H, NH),
7.81 (d, J = 8.30 Hz, 2H, BrPh), 7.76 (d, J = 1.95 Hz, 1H, furan C5-H), 7.48 (d, J = 8.79 Hz,
2H, BrPh), 6.53 (dd, J = 3.41 ; 1.96 Hz, 1H, furan C4-H), 6.31 (d, J = 3.42 Hz, 1H, furan C3-
H), 5.83-5.76 (m, 1H, CH=), 5.18 (d, J = 17.57 Hz, 1H, =CH2 trans), 5.14 (d, J = 9.76 Hz, 1H,
=CH2 cis), 4.22 (d, J = 5.37 Hz, 2H, N-CH2), 4.06 ; 4.00 (2s, 4H, SCH2).
2-((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)-N’-(3-phenyl-4-
oxothiazolidin-2-ylidene)acetohydrazide (6e)
White solid, m.p. 222-223 oC, yield: 82.35%. Anal. Calcd. for C23H17BrN6O3S2: C, 48.51; H,
3.00; N, 14.75 %. Found: C, 47.84; H, 2.82; N, 14.83 %. IR υmax (KBr, cm-1): 3473 (N-H
stretching), 1727 (C=O ring stretching), 1670 (C=O stretching), 1569, 1512, 1490, 1443
1
(C=N, C=C stretching). H-NMR (500 MHz) (DMSO-d6/TMS) δ (ppm): 10.49 (s, 1H, NH),
7.78 (d, J = 8.30 Hz, 2H, BrPh), 7.75 (d, J = 1.95 Hz, 1H, furan, C5-H), 7.50-7.29 (m, 7H, ar),
6.53 (dd, J = 3.42 ; 1.96 Hz, 1H, furan C4-H), 6.29 (d, J = 3.42 Hz, 1H, furan C3-H), 4.17 ;
3.95 (2s, 4H, SCH2).
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4.1.5 General procedure for the synthesis of 5-(((4-(4-bromophenyl)-5-(furan-2-yl)-4H-
1,2,4-triazol-3-yl)thio)methyl)-4-(alkyl/alkenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones
(7a-d)
A solution of 0.005 mol 2-(2-((4-(4-bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-
yl)thio)acetyl)-N-(alkly/aryl)hydrazinecarbothioamide in 2N aqueous NaOH (20 mL) was
heated under reflux for 2h. After cooling, the reaction mixture was acidified by the addition of
12.5% aqueous HCI. The precipitate thus obtained was collected by filtration, washed with
water several times and purified by recrystallization from EtOH.
5-(((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-4-methyl-2,4-
dihydro-3H-1,2,4-triazole-3-thione (7a)
o
White solid, m.p. 218-220 C, yield: 75.70%. Anal. Calcd. for C16H13BrN6OS2: C, 42.76; H,
2.91; N, 18.70 %. Found: C, 42.62; H, 2.96; N, 18.19 %. IR υmax (KBr, cm-1): 3420 (N-H
1
stretching), 1570, 1491, 1451, 1400 (C=N, C=C stretching). H-NMR (500 MHz) (DMSO-
d6/TMS) δ (ppm): 13.59 (s, 1H, NH), 7.80 (d, J = 8.79 Hz, 2H, BrPh), 7.78 (d, J = 1.95, 1H,
furan C5-H), 7.41 ; 7.36 (2d, J = 8.78 Hz, 2H, BrPh), 6.53 (dd, J = 3.42 ; 1.95 Hz, 1H, furan
C4-H), 6.32 ; 6.11 (2d, J = 3.41 ; 4.39 Hz, 1H, furan C3-H), 4.35 (s, 2H, SCH2), 3.45 (s, 3H,
NCH3). 13C NMR (APT) (125 MHz, δ ppm, DMSO-d6): 168.84; 167.82 (C=S), 149.46;
149.12 (Fur C2), 148.06 (FurTR C5), 145.92; 145.69 (Fur C5), 143.39 (TR C5), 141.13;
140.15 (TR C3), 134.13 (BrPh C1), 133.43; 133.11 (BrPh C3,5), 131.46; 130.22 (BrPh C2,6),
124.29; 123.79 (BrPh C4), 113.21; 112.28 (fur C3,4), 30.51 (CH3), 27.99 (CH2). EIMS [m/z
(%)]: 450 [(M+2), 10], 448 (M+, 8), 323 (99), 321 (100), 269 (25), 267 (26), 250 (6), 248 (5).
5-(((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-4-ethyl-2,4-
dihydro-3H-1,2,4-triazole-3-thione (7b)
o
White solid, m.p. 258-259 C, yield: 93.28%. Anal. Calcd. for C17H15BrN6OS2: C, 44.06; H,
3.26; N, 18.13 %. Found: C, 44.59; H, 2.98; N, 17.61 %. IR υmax (KBr, cm-1): 3439 (N-H
1
stretching), 1569, 1491, 1450, 1400 (C=N, C=C stretching). H-NMR (500 MHz) (DMSO-
d6/TMS) δ (ppm): 13.58 (s, 1H, NH), 7.80 (d, J = 8.78 Hz, 2H, BrPh), 7.78 (d, J = 1.96 Hz,
1H, furan C5-H), 7.42 (d, J = 8.79 Hz, 2H, BrPh), 6.52 (dd, J = 3.41 ; 1.96 Hz, 1H, furan C4-
H), 6.11 (d, J = 3.42 Hz, 1H, furan C3-H), 4.35 (s, 2H, SCH2), 3.92 (q, J = 7.32 Hz, 2H, N-
CH2), 1.14 ; 1.06 (2t, J = 7.32 Hz, 3H, CH3).
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5-(((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-4-propyl-2,4-
dihydro-3H-1,2,4-triazole-3-thione (7c)
o
White solid, m.p. 263-264 C, yield: 92.78%. Anal. Calcd. for C18H17BrN6OS2: C, 45.28; H,
3.59; N, 17.60 %. Found: C, 44.99; H, 2.88; N, 17.11 %. IR υmax (KBr, cm-1): 3447 (N-H
1
stretching), 1526, 1492, 1457, 1402 (C=N, C=C stretching). H-NMR (500 MHz) (DMSO-
d6/TMS) δ (ppm): 13.59 (s, 1H, NH), 7.79 (d, J = 8.79 Hz, 2H, BrPh), 7.77 (d, J = 1.95 Hz,
1H, furan C5-H), 7.42 (d, J = 8.29 Hz, 2H, BrPh), 6.52 (dd, J = 3.42 ; 1.95 Hz, 1H, furan C4-
H), 6.11 (d, J = 3.42 Hz, 1H, C3-H), 4.36 (s, 2H, SCH2), 3.43 (t, J = 6.83 Hz, 2H, N-CH2),
1.73-1.47 (m, 2H, CH2CH3), 1.04 (t, J = 6.84 Hz, 3H, CH3).
5-(((4-(4-Bromophenyl)-5-(furan-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-4-allyl-2,4-
dihydro-3H-1,2,4-triazole-3-thione (7d)
o
White solid, m.p. 249-250 C, yield: 98.75%. Anal. Calcd. for C18H15BrN6OS2: C, 45.47; H,
3.18; N, 17.67 %. Found: C, 44.93; H, 3.05; N, 17.56 %. IR υmax (KBr, cm-1): 3422 (N-H
1
stretching), 1570, 1491, 1449,1400 (C=N, C=C stretching). H-NMR (500 MHz) (DMSO-
d6/TMS) δ (ppm): 13.69 (s, 1H, NH), 7.80 (d, J = 8.30 Hz, 2H, BrPh), 7.78 (d, J = 1.96 Hz,
1H, furan C5-H), 7.42 (d, J = 8.78 Hz, 2H, BrPh), 6.52 (dd, J = 3.42 Hz ; 1.95 Hz, 1H, furan
C4-H), 6.11 (d, J = 2.93 Hz, 1H, furan C3-H), 5.90-5.60 (m, 1H, CH=), 5.15 (d, J = 9.28 Hz,
1H, = CH2 cis), 5.02 (d, J = 18.54 Hz, 1H, = CH2 trans), 4.62 (d, J = 5.37 Hz, 2H, N-CH2),
4.33 (s, 2H, SCH2).
4.2 Biological activity assays
The stock solutions of the title compounds were prepared by dissolving them in dimethyl
sulfoxide with a density of 3200 µg/mL. RPMI 1640 medium was utilized to obtain the final
concentration for Candida species as well as the dermatophytes. Besides, Mueller-Hinton
broth was utilized for obtaining the aimed concentration of the tested bacterias. In the end, the
concentrations of the samples were diminished to 1%.
4.2.1 Antibacterial activity
Microbroth dilution method was utilized to detect the minimum inhibitory concentrations.
National Committee for Clinical Laboratory Standards (NCCLS) recommendations were
followed while performing the microbroth dilution method.[56] Mueller-Hinton broth was
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utilized as the test analysis medium. Inoculums with an amount of 5 x 105 CFU cm-3 were
applied for each well. The dilutions of the title compounds, whose concentrations were
diminished for two times (64-0.25 µg/mL), were prepared. Besides, additional dilutions were
applied for antibiotic standards (0.12-0.015 µg/mL). The incubation process of the plates was
performed in an ambient air incubator. The incubation process was conducted for 16-20h at
o
95 F temperature. The minimum concentration of the analyzed compounds that inhibits
visible growth was stated as the minimum inhibitory concentration value.
4.2.2 Antifungal activity
4.2.2.1 Antifungal activity for Candida species
Microbroth dilution method was utilized to detect the minimum inhibitory concentrations.
National Committee for Clinical Laboratory Standards (NCCLS) recommendations were
followed while performing the microbroth dilution method.[57] RPMI 1640 was utilized to
obtain RPMI broth. For this, 0.3-gram glutamine was added for each liter of RPM 1640. Then
buffering was applied with 3-(N-morpholino)-propanesulfonic acid (MOPS), and the pH was
set as 7.0. Afterward, the inoculum suspension was set by 1% dilution of 0.5 McFarland
standards yeast solution in 0.85% saline followed by 0.05 dilution in RPMI broth.
Title dilutions of the title compounds were prepared from 64 to 0.25 µg/mL with the
suspension of the inoculum. Superior dilutions were applied for the standard compound,
itraconazole (0.12-0.015 µg/mL). The incubation process of the plates was performed in an
ambient air incubator. The incubation process was conducted for 48h at a temperature of 95
oF. The minimum concentration of the analyzed compounds that inhibits visible growth, was
defined as the minimum inhibitory concentration value.
4.2.2.2 Antifungal activity for dermatophytes
The Microdilution method was utilized by following the classical protocol of NCCLS.[56] L-
glutamine and RPMI 1640 were buffered with 3-(N-morpholino)-propanesulfonic acid. Then,
the pH of the medium was set as 7.0 at a temperature of 77 oF. The process for the preparation
of the suspensions of the inoculums was conducted by following the NCCLS guidelines[58]
and previously reported procedure.[59]
The separations were cultured on potato dextrose agar plates at 82.4 oF for two weeks. Then, 1
cm-3 of 0.85% saline were added to obtain a suspension of the fungal colonies. The obtained
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suspension was transferred to a sterile tube. The massive compounds were let to settle for 20
minutes at 69.8 oF. Then the upper suspension was mixed for 15 seconds by utilizing a vortex.
The composed turbidness of supernatants was analyzed spectrophotometrically at 530 nm
wavelength. The obtained suspensions were diluted 2% in RPMI to get the end sizes of
inoculum (from 0.4 x 104 to 5 x 104 CFU cm-3). After the preparation of the microdilution
o
plates, they were frozen at -94 F until the usage time. Rows from 2 to 12 included a diverse
series of drug solutions in 100 µL volumes and 1st row included 100 µL drug-free medium,
which was used as growth control. The inoculations were performed for each well on the day
of the analysis with 100 µL volumes of the corresponding inoculum. By this step, the final
analysis concentrations were obtained. The incubation process was performed for the
microplates for 1 week at a temperature of 82.4 oF. At the end of 1 week, the microplates were
evaluated visually with the help of an inverted reading mirror for dermatophytes. For all
compounds, minimum inhibitory concentration was defined as the minimal concentration
displaying 100% inhibition of growth.
ACKNOWLEDGEMENTS
This work was supported by Istanbul University Research Project (Project Number: 52074).
CONFLICT OF INTEREST
The authors declared that they have no conflict of interest.
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Entry for the Table of Contents
Graphic for Table of Contents
Compound 6d
Compound 7c
Compound 7d
The most active compounds against the tested microorganisms
Synthesis
hydrazinecarbothioamide,
of
12
novel
Antibacterial and antifungal
activity evaluation of 12 novel
compounds against
microorganisms
9 diverse
4-thiazolidinone and 1,2,4-
triazole-3-thione derivatives
Text for Table of Contents
A series of novel hydrazinecarbothioamide, 4-thiazolidinone and 1,2,4-triazole-3-thione
derivatives were synthesized and assayed for their antibacterial and antifungal activities
against 9 diverse microorganisms (S. aureus (ATCC 29213), E. coli (ATCC 25922) and P.
aeruginosa (ATCC27853), C. albicans (ATCC10231), C. krusei (ATCC 6258), C.
parapsilosis (ATCC 22019), M. gypseum (NCPF580), T. metagrophytes var. erinacei (NCPF
375) and T. tonsurans (NCPF 245). Some compounds displayed remarkable antibacterial and
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antifungal activity against the tested microorganisms. Particularly, 4-propyl and allyl
substitution of 1,2,4-triazole-3-thiones and 3-allyl substitution of 4-thiazolidinones increased
the antimicrobial activities.
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